Peptide Functionalisation Through Isoimide Intermediates

© 2020 Ameer Badri TareshAbstract We have developed new synthetic methods for the modification of peptides, exploiting acyl transfer reactions of isoimides. We have developed a new approach for the chemoselective synthesis of N-glycopeptides, using a Ag(I)-promoted coupling. We have successfully applied the Ag(I)-promoted coupling of aspartic acid containing peptide thioamides and glycosyl amines to the chemoselective synthesis of N glycosylated asparaginyl motifs. The methodology employs peptides possessing a thioamide group adjacent to the aspartic acid residue. Intramolecular Ag(I)-promoted coupling of the aspartic acid side-chain carboxylate with the thioamide generates an isoimide intermediate that is trapped by an external glycosyl amine to form an amide bond and generate an N-glycoasparagine. A range of thiopeptides containing unprotected carboxylates undergo Ag(I)-promoted coupling with glycosyl amine derivatives, leading to the preparation of N-glycosylated asparaginyl peptides. Moreover, this method enables the site-selective generation of N-glycosyl asparagines in peptides possessing multiple unprotected carboxylate side chains groups. We have also investigated analogous reactions of peptide thioamides possessing a lysine residue, wherein coupling of the aspartate and lysine side chains generates Lys–Asp side-chain lactam-linked peptides. Thiopeptides with i,i+2, i,i+3, and i,i+4-spaced Lys and Asp residues undergo intramolecular Ag(I)-promoted coupling to give lactam bridged peptides. The final chapter describes initial investigations towards elaborating the Ag(I)-promoted reaction to the synthesis of 18F-radiolabelled peptides. The Ag(I)-promoted method was shown to be effective for the coupling of [18F]-fluorobenzoic acid with thiopeptides, generating18F-fluorobenzoylated peptides